Insulin-like growth factor II plays a prominent role in malignant transformation by activating the IGF-I receptor. Activated IGF-IR promotes malignant growth by stimulating cellular proliferation and by inhibiting apoptosis. IGF-II also binds to the mannose 6-phosphate/IGF-II receptor (IGF-IIR), a transport molecule controlling IGF-II availability during embryogenesis. We hypothesize that the IGF-IIR also limits IGF-II signalling in malignant cells. In an autocrine model of IGF-II signalling, we demonstrated that IGF-IIR inhibited the extracellular accumulation of IGF-II, thereby reducing IGF-IR-dependent cellular proliferation and anchorage-independent growth. These observations lead us to propose the following research aims: l) To confirm that the IGF-IIR acts as an IGF-II antagonist by overexpressing the IGF-IIR with a panel of mutant IGF mutant peptides with altered receptor affinity. We anticipate that IGF-IIR overexpression, only when coexpressed with high IGF-IIR avidity ligands, will repress extracellular IGF availability; 2) IGF-IIR overexpression, suppressing IGF-II signalling, may provide a mechanism to reverse or inhibit IGF-II-dependent malignancy. We will test this hypothesis in IGF-II expressing sarcoma cell lines, 3) The third aim will further explore the antagonistic actions of IGF-IIR, employing receptor mutants with altered ligand binding and transport properties. Given that autocrine IGF-II expression is a prominent feature of sarcomas, for which treatment options are limited, investigation of a novel mechanism of growth factor suppression serves the long term goal of designing new therapeutic approaches.